Analysis of DNA methylation and histone modification profiles of liver-specific transporters.
Tissue-specific expression of transporters is tightly linked with their physiological functions through the regulation of the membrane transport of their substrates. We hypothesized that epigenetic regulation underlies the tissue-specific expression of mouse liver-specific transporters (Oatp1b2/Slco1b2, Ntcp/Slc10a1, Bsep/Abcb11, and Abcg5/g8). We examined their DNA methylation and histone modification profiles near the transcriptional start site (TSS) in the liver, kidney, and cerebrum. Genome-wide DNA methylation profiling with tissue-dependent differentially methylated region profiling with restriction tag-mediated amplification and subsequent bisulfite genomic sequencing demonstrated that the CpG dinucleotides around the TSS of Oatp1b2 (from -515 to +149 CpGs), Ntcp (from -481 to +495 CpGs), Bsep (from -339 to +282 CpGs), and Abcg5/g8 (from -161 to +5 CpGs for Abcg5, i.e., from -213 to -48 CpGs for Abcg8) were hypomethylated in the liver and hypermethylated in the kidney and cerebrum. The opposite pattern was observed for Pept2/Slc15a2 (from -638 to +4 CpGs), which was expressed in the kidney and cerebrum but not in the liver. These DNA methylation profiles are consistent with the tissue distribution of these transporters. A chromatin immunoprecipitation assay demonstrated that the histone H3 associated with Oatp1b2, Ntcp, Bsep, and Abcg5/g8 promoters was hyperacetylated in the liver but was acetylated very little in the kidney and cerebrum, whereas the upstream region of Pept2 was hyperacetylated only in the kidney and cerebrum. These results suggest the involvement of epigenetic systems in the tissue-specific expression of mouse transporters Oatp1b2, Ntcp, Bsep, Abcg5/g8, and Pept2.


Electroacupuncture brain protection during ischemic stroke: A role for the parasympathetic nervous system.
The demand for using parasympathetic activation for stroke therapy is unmet. In the current study, we investigated whether the neuroprotection provided by electroacupuncture (EA) in an experimental stroke model was associated with activation of the parasympathetic nervous system (PNS). The results showed that parasympathetic dysfunction (PD), performed as unilateral vagotomy combined with peripheral atropine, attenuated both the functional benefits of EA and its effects in improving cerebral perfusion, reducing infarct volume, and hindering apoptosis, neuronal and peripheral inflammation, and oxidative stress. Most importantly, EA rats showed a dramatically less reduction in the mRNA level of choline acetyltransferase, five subtypes of muscarinic receptors and α7nAChR, suggesting the inhibition of the impairment of the central cholinergic system; EA also activated dorsal motor nucleus of the vagus, the largest source of parasympathetic pre-ganglionic neurons in the lower brainstem (detected by c-fos immunohistochemistry), and PD suppressed these changes. These findings indicated EA may serve as an alternative modality of PNS activation for stroke therapy.


Eyelid reconstruction: an oculoplastic surgeon's perspective.
The eyelids provide structural support for the globe and play an essential role in protecting and lubricating the eye. Trauma, tumor resection, or congenital defects may compromise eyelid function. The goals of eyelid reconstruction are to restore the function of the eyelids and lacrimal drainage apparatus, provide adequate protection for the globe, and achieve reasonable cosmetic results.


Managing problem behaviors of elderly patients.
Professional as well as nonprofessional staff who work with the elderly in nursing homes must be reminded repeatedly that most problem behaviors are symptoms of such underlying problems as unresolved conflicts, the loss of normal, appropriate life roles, and the anticipation of illness and death. The author describes how those problems are reflected in such "senile" behaviors as incoherence, incontinence, ritualism, and inappropriate sexual behaviors. She believes the concept of personality regression under stress is a useful framework for helping staff understand and manage such behaviors. She illustrates how nonprofessional staff can help patients achieve a more satisfactory adjustment by using certain behavior modification techniques, by roleplaying, and by identifying feelings responsible for porblem behaviors and helping patients ventilate them.


Is the Collapse of the Respiratory Center in the Brain Responsible for Respiratory Breakdown in COVID-19 Patients?
Following the identification of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, we are now again facing a global highly pathogenic novel coronavirus (SARS-CoV-2) epidemic. Although the lungs are one of the most critically affected organs, several other organs, including the brain may also get infected. Here, we have highlighted that SARS-CoV-2 might infect the central nervous system (CNS) through the olfactory bulb. From the olfactory bulb, SARS-CoV-2 may target the deeper parts of the brain including the thalamus and brainstem by trans-synaptic transfer described for many other viral diseases. Following this, the virus might infect the respiratory center of brain, which could be accountable for the respiratory breakdown of COVID-19 patients. Therefore, it is important to screen the COVID-19 patients for neurological symptoms as well as possibility of the collapse of the respiratory center in the brainstem should be investigated in depth.


Testing of two-dimensional Gaussian processes by sample cross-covariance function.
In this paper, we address the issue of testing two-dimensional Gaussian processes with a defined cross-dependency structure. Multivariate Gaussian processes are widely used in various applications; therefore, it is essential to identify the theoretical model that accurately describes the data. While it is relatively straightforward to do so in a one-dimensional case, analyzing multi-dimensional vectors requires considering the dependency between the components, which can significantly affect the efficiency of statistical methods. The testing methodology presented in this paper is based on the sample cross-covariance function and can be considered a natural generalization of the approach recently proposed for testing one-dimensional Gaussian processes based on the sample autocovariance function. We verify the efficiency of this procedure on three classes of two-dimensional Gaussian processes: Brownian motion, fractional Brownian motion, and two-dimensional autoregressive discrete-time process. The simulation results clearly demonstrate the effectiveness of the testing methodology, even for small sample sizes. The theoretical and simulation results are supported by analyzing two-dimensional real-time series that describe the main risk factors of a mining company, namely, copper price and exchange rates (USDPLN). We believe that the introduced methodology is intuitive and relatively simple to implement, and thus, it can be applied in many real-world scenarios where multi-dimensional data are examined.


Total network controllability analysis discovers explainable drugs for Covid-19 treatment.
The active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural controllability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets. We developed an efficient algorithm to identify all control hubs, applying it to a largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach's effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients. Our findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery. Our new approach is general and applicable to repurposing drugs for other diseases.


Passive radiative cooling below ambient air temperature under direct sunlight.
Cooling is a significant end-use of energy globally and a major driver of peak electricity demand. Air conditioning, for example, accounts for nearly fifteen per cent of the primary energy used by buildings in the United States. A passive cooling strategy that cools without any electricity input could therefore have a significant impact on global energy consumption. To achieve cooling one needs to be able to reach and maintain a temperature below that of the ambient air. At night, passive cooling below ambient air temperature has been demonstrated using a technique known as radiative cooling, in which a device exposed to the sky is used to radiate heat to outer space through a transparency window in the atmosphere between 8 and 13 micrometres. Peak cooling demand, however, occurs during the daytime. Daytime radiative cooling to a temperature below ambient of a surface under direct sunlight has not been achieved because sky access during the day results in heating of the radiative cooler by the Sun. Here, we experimentally demonstrate radiative cooling to nearly 5 degrees Celsius below the ambient air temperature under direct sunlight. Using a thermal photonic approach, we introduce an integrated photonic solar reflector and thermal emitter consisting of seven layers of HfO2 and SiO2 that reflects 97 per cent of incident sunlight while emitting strongly and selectively in the atmospheric transparency window. When exposed to direct sunlight exceeding 850 watts per square metre on a rooftop, the photonic radiative cooler cools to 4.9 degrees Celsius below ambient air temperature, and has a cooling power of 40.1 watts per square metre at ambient air temperature. These results demonstrate that a tailored, photonic approach can fundamentally enable new technological possibilities for energy efficiency. Further, the cold darkness of the Universe can be used as a renewable thermodynamic resource, even during the hottest hours of the day.


The geometry of the cruciate ligaments in the canine and equine knee joint, a Tchebychev mechanism.
The ratio between the length of the anterior and posterior cruciate ligaments and the distance between their femoral and tibial attachments in the canine and equine knee joint reveals that these structures form a Tchebychev mechanism for parallel motion.


Neuroticism and extroversion in suicide attempters aged 75 and above and a general population comparison group.
Personality traits have been shown to influence suicidal behaviour but the literature on 'older' elderly is sparse. The aim was to compare neuroticism and extroversion in hospitalized suicide attempters aged 75 and above and a general population comparison group. Seventy-two hospitalized suicide attempters (mean age 81 years) were interviewed. Comparison subjects were drawn from participants in population studies on health and ageing. Participants completed the Eysenck Personality Inventory (EPI) and symptoms of depression were rated with the Montgomery-Asberg Depression Rating Scale (MADRS). Depression diagnoses were made in accordance with Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Attempters scored higher on the neuroticism scale than comparison subjects (mean = 9.9 vs. 7.6, t = 3.74, df = 358, p < 0.001) and lower on the extroversion scale (mean = 10.8 vs. 12.0; t = -2.76, df = 358, p = 0.006). While these differences did not remain after adjustment for major depression, attempters with minor depression were less neurotic than comparison subjects with this diagnosis (mean = 6.6 vs. 11.1, t = -3.35, df = 63, p = 0.001) and a negative association with neuroticism remained in a multivariate model. In conclusion cases scored higher on neuroticism and lower on extroversion compared to comparison subjects. The finding that attempters with minor depression were less neurotic than comparison subjects with this diagnosis was unexpected and needs to be examined in larger samples.


Evaluation of psychotherapeutic interpretations : an example of the application of the phenomenological method to discovery-based psychotherapy research.
If much psychotherapy literature goes unread and unused by therapists, one reason may be the apparent irrelevance of theory-derived hypotheses to actual practice. Methods that uncover tacit knowledge that practicing therapists already possess can provide the empirical basis for more relevant theories and the testing of more meaningful hypotheses. This study demonstrates application of the phenomenological method to the question of evaluating psychotherapy. To discover how experienced psychotherapists evaluate interpretations made in actual psychotherapy sessions, therapists were asked to evaluate such interpretations from videotapes; analysis of responses yielded a set of 10 dimensions of evaluation. Such methods offer both practical utility and a source of theoretical growth anchored in the real world of the practicing therapist.


Quantitative design rules for protein-resistant surface coatings using machine learning.
Preventing biological contamination (biofouling) is key to successful development of novel surface and nanoparticle-based technologies in the manufacturing industry and biomedicine. Protein adsorption is a crucial mediator of the interactions at the bio - nano -materials interface but is not well understood. Although general, empirical rules have been developed to guide the design of protein-resistant surface coatings, they are still largely qualitative. Herein we demonstrate that this knowledge gap can be addressed by using machine learning approaches to extract quantitative relationships between the material surface chemistry and the protein adsorption characteristics. We illustrate how robust linear and non-linear models can be constructed to accurately predict the percentage of protein adsorbed onto these surfaces using lysozyme or fibrinogen as prototype common contaminants. Our computational models could recapitulate the adsorption of proteins on functionalised surfaces in a test set with an r2 of 0.82 and standard error of prediction of 13%. Using the same data set that enabled the development of the Whitesides rules, we discovered an extension to the original rules. We describe a workflow that can be applied to large, consistently obtained data sets covering a broad range of surface functional groups and protein types.


Photoinduced Borylation of the Inert C(sp3)-O Bond of Alkyl Heteroaryl Ethers.
A photoinduced reductive Calkyl-O borylation of alkyl heteroaryl ethers with very negative reduction potential in the presence of 4-dimethylaminopyridine (DMAP) and bis(catecholato)diborane(B2cat2) was developed. Despite the high reducing power, various substrates with liable functional groups were well-tolerated as well as ethers derived from natural products and medicinal-relevant compounds. Mechanistic investigation implied that an intra-single electron transfer process in an electron donor-acceptor complex formed from ethers with the adduct of B2cat2 and DMAP should be involved.


Adrenalectomy-induced alterations in glucagon binding and lipolysis in isolated rat adipocytes.
Adipocytes from adrenalectomized rats nearly lost their lipolytic response to glucagon concomitant with a 90% decrease in the number of glucagon receptors per cell. Quantitative analysis of the relation between amount of cell-bound glucagon and hormone-stimulated lipolysis revealed that the ability of the remaining 10% of glucagon receptors to induce lipolysis was not impaired. Binding of the beta-adrenergic antagonist [3H]dihydroalprenolol and maximal lipolysis induced by (-)-isoproterenol, (Bu)2cAMP, 3-isobutyl-1-methylxanthine, and adenosine deaminase were reduced only 10 to 20% after adrenalectomy. Furthermore, glucagon-stimulated cAMP production was greatly decreased in adrenalectomized animals, but isoproterenol-stimulated cAMP production was not. Hydrocortisone replacement in adrenalectomized rats only partially prevented the loss of glucagon receptors and glucagon effects on both cAMP production and lipolysis. These findings suggest that lipolytic cascade distal to hormone receptors was not greatly impaired in adipocytes after adrenalectomy and that the unresponsiveness of these cells to glucagon was mostly due to a marked reduction in the number of glucagon receptors.


Effect of gender on the social and psychological adjustment of cancer patients.
The purpose of this article is to examine gender differences in social and psychological adjustment among cancer patients. The social adjustment and psychological distress of 49 patients (34 women and 15 men) undergoing active medical care (chemotherapy and radiation) were assessed. Socio-demographic and medical parameters were also examined to account for differences in adjustment. Three questionnaires were used: A personal information questionnaire; a Psychosocial Adjustment to Illness Scale (PAIS-SR) (Derogatis & Lopez, 1983); and a psychological distress one (BSI) (Derogatis & Spencer, 1982). Significant differences were found between men and women patients in several dimensions of the social adjustment, psychological distress and medical variables. Possible explanations, recommendations for further research and clinical intervention are suggested.


Panic disorder in clinically referred children and adolescents.
The present study examined the frequency and characteristics of panic disorder in children and adolescents who had been referred to a pediatric psychopharmacology clinic. Of the 280 children and adolescents evaluated in this clinic, 35 were diagnosed with panic disorder using a semi-structured clinical interview (K-SADS) and other objective measures. Approximately half of the youngsters with panic disorder also met criteria for the diagnosis of agoraphobia. There was extensive comorbidity between panic disorder and other internalizing and externalizing disorders. Parents reported clinically significant levels of child symptomatology on the CBCL. Teacher-and child-reported symptomatology on the CBCL was within the normal range. At the same time, it was notable that no child had been referred specifically for evaluation or treatment of panic disorder or agoraphobia. Implications for clinical assessment/identification and treatment are discussed.


Entrainer effects on enantiodifferentiating photocyclization of 5-hydroxy-1,1-diphenylpentene in near-critical and supercritical carbon dioxide.
Enantiodifferentiating photocyclization of 5-hydroxy-1,1-diphenyl-1-pentene (1) sensitized by bis(1,2;4,5-di-O-isopropylidene-α-fructopyranosyl) 1,4-naphthalenedicarboxylate (2) was performed in near-critical and supercritical carbon dioxide media containing organic entrainers to obtain a chiral tetrahydrofuran derivative (3) in enantiomeric excess (ee) higher than those obtained in conventional organic solvents. Interestingly, the entrainer-driven ee enhancement did not depend on the entrainer polarity, which is in contrast to the behavior of the ee observed upon selective solvation in nonpolar organic solvents. This indicates that entrainer clustering around the intervening exciplex is essential in order to keep the intimate sensitizer-substrate contact within the exciplex. Therefore, the clustering itself, rather than its property, is more crucial to prevent the dissociative diffusion to gaseous CO(2). The wider allowance in choosing the entrainer enables us to use more "green" solvents for achieving the ee enhancement, while reducing the environmental risk.


Increased Dairy Product Intake Modifies Plasma Glucose Concentrations and Glycated Hemoglobin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Dairy product intake is inversely associated with the risk of type 2 diabetes (T2D) in numerous cohort studies; yet, the beneficial effects of increased dairy product intake on T2D risk factors such as fasting plasma glucose, fasting insulin, insulin resistance with the homeostasis model assessment, and glycated hemoglobin (HbA1c) remain inconclusive in clinical trials. The objective of this study was to systematically review clinical trials observing the effects of elevated compared with minimal intake of dairy products on T2D risk factors in subjects without diabetes. Five databases [Medline, EMBASE, Central, CINAHL, AMED (Allied and Complementary Medicine)] were searched to identify randomized controlled trials that used elevated quantities of dairy products from ruminant sources in comparison with a lower intake in control groups. The review outcomes were fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and HbA1c. Risk of bias and quality of evidence according to Grading of Recommendations Assessment, Development, and Evaluation were addressed. From the 10,627 citations screened, 44 studies (3016 participants) were included, 38 of which were used in the meta-analyses. Fasting glucose was positively associated with elevated dairy intake [34 studies, n = 2678; mean difference (MD): 0.07 mmol/L; 95% CI: 0.01, 0.12 mmol/L; P = 0.01, I2 = 23%]. Fasting insulin (29 studies, n = 1902; MD: -2.97 pmol/L; 95% CI: -7.05, 1.10 pmol/L; P = 0.15, I2 = 21%) and HOMA-IR (13 studies, n = 840; standardized MD: -0.07; 95% CI: -0.26, 0.12; P = 0.49, I2 = 38%) were not associated with elevated dairy consumption. HbA1c was negatively associated with elevated dairy product intake in 4 studies (n = 512; MD: -0.09%; 95% CI: -0.09%, -0.03%; P = 0.005, I2 = 0%). Most studies had high risk of bias and the quality of evidence was very low or low. In conclusion, evidence suggests that elevated dairy product intake is associated with increased fasting plasma glucose concentrations together with reduced HbA1c in nondiabetic subjects. Hence, the clinical significance of these results remains uncertain. Additional well-designed, long-term studies are required.


Edge-plane-rich nitrogen-doped carbon nanoneedles and efficient metal-free electrocatalysts.
CNN news: N-doped carbon nanoneedles (CNNs) are synthesized by self-assembling core-shell nanostructures and nanoreactors around cellulose nanoneedles, and subsequent graphitization. The resulting graphitic nanoneedles (see picture) have well-organized graphitic multi-layers and large proportions of N-doped edge planes. The materials serve as efficient metal-free electrocatalysts for hydrazine oxidation.


Knockout of floral and meiosis genes using CRISPR/Cas9 produces male-sterility in Eucalyptus without impacts on vegetative growth.
Eucalyptus spp. are widely cultivated for the production of pulp, energy, essential oils, and as ornamentals. However, their dispersal from plantings, especially when grown as an exotic, can cause ecological disruptions. To provide new tools for prevention of sexual dispersal by pollen as well as to induce male-sterility for hybrid breeding, we studied the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated knockout of three floral genes in both FT-expressing (early-flowering) and non-FT genotypes. We report male-sterile phenotypes resulting from knockout of the homologs of all three genes, including one involved in meiosis and two regulating early stages of pollen development. The targeted genes were Eucalyptus homologs of REC8 (EREC8), TAPETAL DEVELOPMENT AND FUNCTION 1 (ETDF1), and HECATE3 (EHEC3-like). The erec8 knockouts yielded abnormal pollen grains and a predominance of inviable pollen, whereas the etdf1 and ehec3-like knockouts produced virtually no pollen. In addition to male-sterility, both erec8 and ehec3-like knockouts may provide complete sterility because the failure of erec8 to undergo meiosis is expected to be independent of sex, and ehec3-like knockouts produce flowers with shortened styles and no visible stigmas. When comparing knockouts to controls in wild-type (non-early-flowering) backgrounds, we did not find visible morphological or statistical differences in vegetative traits, including average single-leaf mass, stem volume, density of oil glands, or chlorophyll in leaves. Loss-of-function mutations in any of these three genes show promise as a means of inducing male- or complete sterility without impacting vegetative development.


Neurokinin Bs and neurokinin B receptors in zebrafish-potential role in controlling fish reproduction.
The endocrine regulation of vertebrate reproduction is achieved by the coordinated actions of several peptide neurohormones, tachykinin among them. To study the evolutionary conservation and physiological functions of neurokinin B (NKB), we identified tachykinin (tac) and tac receptor (NKBR) genes from many fish species, and cloned two cDNA forms from zebrafish. Phylogenetic analysis showed that piscine Tac3s and mammalian neurokinin genes arise from one lineage. High identity was found among different fish species in the region encoding the NKB; all shared the common C-terminal sequence. Although the piscine Tac3 gene encodes for two putative tachykinin peptides, the mammalian ortholog encodes for only one. The second fish putative peptide, referred to as neurokinin F (NKF), is unique and found to be conserved among the fish species when tested in silico. tac3a was expressed asymmetrically in the habenula of embryos, whereas in adults zebrafish tac3a-expressing neurons were localized in specific brain nuclei that are known to be involved in reproduction. Zebrafish tac3a mRNA levels gradually increased during the first few weeks of life and peaked at pubescence. Estrogen treatment of prepubertal fish elicited increases in tac3a, kiss1, kiss2, and kiss1ra expression. The synthetic zebrafish peptides (NKBa, NKBb, and NKF) activated Tac3 receptors via both PKC/Ca(2+) and PKA/cAMP signal-transduction pathways in vitro. Moreover, a single intraperitoneal injection of NKBa and NKF significantly increased leuteinizing hormone levels in mature female zebrafish. These results suggest that the NKB/NKBR system may participate in neuroendocrine control of fish reproduction.


An efficient one-pot synthesis of benzothiazolo-4β-anilino-podophyllotoxin congeners: DNA topoisomerase-II inhibition and anticancer activity.
An efficient one-pot iodination methodology for the synthesis of benzothiazolo-4β-anilino-podophyllotoxin (5a-h) and benzothiazolo-4β-anilino-4-O-demethylepipodophyllotoxin (6a-h) congeners has been successfully developed by using zirconium tetrachloride/sodium iodide. Interestingly, this protocol demonstrates enhancement of stereoselectivity apart from the improvement in the yields in comparison to previous methods reported for such related podophyllotoxin derivatives. These compounds have been designed and synthesized using association strategy by coupling of 4β-podophyllotoxin and 4β-demethylepipodophyllotoxin with a variety of substituted aminoaryl benzothiazoles. Some of the representative compounds have been evaluated for their cytotoxicity against selected human cancer cell lines and DNA topoisomerase-II inhibition activity.


Availability of autoantigenic epitopes controls phenotype, severity, and penetrance in TCR Tg autoimmune gastritis.
We examined TCR:MHC/peptide interactions and in vivo epitope availability to explore the Th1- or Th2-like phenotype of autoimmune disease in two TCR Tg mouse models of autoimmune gastritis (AIG). The TCR of strains A23 and A51 recognize distinct IA(d)-restricted peptides from the gastric parietal cell H/K-ATPase. Both peptides form extremely stable MHC/peptide (MHC/p) complexes. All A23 animals develop a Th1-like aggressive, inflammatory AIG early in life, while A51 mice develop indolent Th2-like AIG at 6-8 wk with incomplete penetrance. A51 T cells were more sensitive than A23 to low doses of soluble antigen and to MHC/p complexes. Staining with IA(d)/peptide tetramers was only detectable on previously activated T cells from A51. Thus, despite inducing a milder AIG, the A51 TCR displays a higher avidity for its cognate IA(d)/peptide. Nonetheless, in vivo proliferation of adoptively transferred A51 CFSE-labeled T cells in the gastric lymph node was relatively poor compared with A23 T cells. Also, DC from WT gastric lymph node, presenting processed antigen available in vivo, stimulated proliferation of A23 T cells better than A51. Thus, the autoimmune potential of these TCR in their respective Tg lines is strongly influenced by the availability of the peptide epitope, rather than by differential avidity for their respective MHC/p complexes.


Biochemical prevention and treatment of viral infections - a new paradigm in medicine for infectious diseases.
For two centuries, vaccination has been the dominating approach to develop prophylaxis against viral infections through immunological prevention. However, vaccines are not always possible to make, are ineffective for many viral infections, and also carry certain risk for a small, yet significant portion of the population. In the recent years, FDA's approval and subsequent market acceptance of Synagis, a monoclonal antibody indicated for prevention and treatment of respiratory syncytial virus (RSV) has heralded a new era for viral infection prevention and treatment. This emerging paradigm, herein designated "Biochemical Prevention and Treatment", currently involves two aspects: (1) preventing viral entry via passive transfer of specific protein-based anti-viral molecules or host cell receptor blockers; (2) inhibiting viral amplification by targeting the viral mRNA with anti-sense DNA, ribozyme, or RNA interference (RNAi). This article summarizes the current status of this field.


How Milk and Its Proteins Affect Growth, Bone Health, and Weight .
Milk has long been recognized to constitute a complete, well-balanced source of the nutrients and energy required to ensure the proper postnatal growth and development of infants. A growing body of evidence suggests the positive effects of dairy products and particularly of milk proteins on linear growth also in older children, both healthy or during recovery from malnutrition. This evidence led the way to the performance of extensive research aimed to delineate the components of milk and the mechanisms acting to make milk so effective. The present review summarizes the current knowledge regarding the influence of milk and its proteins on linear growth in healthy and malnourished children, focusing also on other important aspects of healthy growth, including bone health, weight status, and body composition. .


Mapper: an intelligent restriction mapping tool.
To determine the most powerful artificial intelligence techniques for automated restriction mapping, and use them to create a powerful multiple-enzyme restriction mapping tool. The most effective search engine utilized model-driven exhaustive search and a form of binary logic pruning based on Pratt's separation theory. Additional experimentation led to the development of an input preprocessing module which significantly speeds up searches, and an output post-processing module which enables users to analyze large solution sets and reduce their apparent complexity. An executable version of the resultant tool, Mapper, can be downloaded from our Web site (http://www.ai.eecs.uic.edu) by selecting the 'Software' option. firstname.lastname@example.com (http://www.ai.eecs.uic.edu/ñelson).


Hepatitis B virus genotypes, expression quantitative trait loci for ZNRD1-AS1 and their interactions in hepatocellular carcinoma.
Genetic variants in zinc ribbon domain-containing 1 antisense RNA 1 (ZNRD1-AS1) have been reported to be associated with development of hepatocellular carcinoma (HCC). We sought to determine the influences of ZNRD1-AS1 polymorphisms and their interactions with Hepatitis B virus (HBV) genotypes on the risk of HCC. In this study, we conducted a large population case-control study with 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers. Three single-nucleotide polymorphisms (SNPs) in ZNRD1-AS1 (rs3757328, rs6940552 and rs9261204) were genotyped using a TaqMan allelic discrimination assay, and the HBV genotypes were identified by multiplex PCR. We found consistently significant associations between the ZNRD1-AS1 rs6940552 and rs9261204 SNPs with an increased risk of HCC (additive genetic model: adjusted OR = 1.16, 95% CI = 1.03-1.32 for rs6940552; adjusted OR =1.20, 95% CI = 1.06-1.35 for rs9261204) and found a borderline association between rs3757328 and HCC risk. Besides, we observed a dose-dependent relationship between increasing numbers of variant alleles of the SNPs and HCC risk (P for trend <0.001). Moreover, we observed a stronger combined effect of the three SNPs on HCC risk among the subjects infected with non-B genotype HBV (adjusted OR = 1.26, 95% CI = 1.05-1.50) compared with HBV B-related genotypes (adjusted OR = 0.89, 95% CI = 0.69-1.15; P= 0.029 for heterogeneity test). We also found that a multiplicative interaction between the variant alleles and the HBV genotype significantly affected HCC susceptibility (P = 0.030). Together, these results indicate that ZNRD1-AS1 may influence HCC risk accompanied by HBV genotypes.


Will genetically modified late blight resistant potatoes be the first GM crops to be approved for commercial growing in Norway?
Last decade's advances in biotechnology, with the introduction of CRISPR, have challenged the regulatory framework for competent authorities all over the world. Hence, regulatory issues related to gene editing are currently high on the agenda both in the EU and in the European Economic Area (EEA) Agreement country of Norway, particularly with regards to sustainable agriculture. During the negotiations on the EEA Agreement, Norway was allowed to retain three extra aims in the Gene Technology Act: "That the production and use of GMO happens in an ethical way, is beneficial to society and is in accordance with the principle of sustainable development". We argue the case that taking sustainability into the decisions on regulating gene edited products could be easier in Norway than in the EU because of these extra aims. Late blight is our chosen example, as a devastating disease in potato that is controlled in Norway primarily by high levels of fungicide use. Also, many of these fungicides are being banned due to negative environmental and health effects. The costs of controlling late blight in Norway were calculated in 2006, and since then there have been new cultivars developed, inflation and an outbreak of war in Europe increasing farm input costs. A genetically modified (GM) cisgenic late blight resistant (LBR) potato presents a possible solution that could reduce fungicide use, but this could still be controversial. This paper aims to discuss the advantages and disadvantages of approving the commercial use of a GM LBR potato cultivar in Norway and compare these against currently used late blight management methods and conventional potato resistance breeding. We argue that a possible route for future regulatory framework could build upon the proposal by the Norwegian Biotechnology Advisory Board from 2019, also taking sustainability goals into account. This could favour a positive response from the Competent Authorities without breeching the European Economic Area (EEA) Agreement. Perhaps the EU could adopt a similar approach to fulfil their obligations towards a more sustainable agriculture?


Evaluation of the association between locomotive syndrome and depressive states: a cross-sectional study.
The Japanese Orthopaedic Association has proposed the term "locomotive syndrome" to designate a condition that places a person at high risk for long-term care. However, in daily clinical practice, even when a diagnosis of locomotive syndrome is made, exercise therapy often cannot be successfully performed in some patients owing to their lack of motivation. We speculated that locomotive syndrome and depressive states co-exist in elderly people. The purpose of this study was to determine the presence or absence of depressive states in older patients aged ≥ 65 years who were diagnosed with locomotive syndrome. A questionnaire survey, the 25-Question Geriatric Locomotive Function Scale and Self-Rating Questionnaire for Depression was conducted. The items of the interview survey were sex, age, and history of treatment for hypertension or diabetes mellitus. For somatometry, height and body weight were measured. Patients diagnosed with locomotive syndrome (LS group) were compared with those without locomotive syndrome (non-LS group). The LS group included 99 patients, mean age was 79.4 years old, while the non-LS group included 101 patients, mean age was 76.3 years old. The number of patients with depressive states and number of females were significantly higher in the LS group. In addition, the LS group was significantly older and shorter. Multivariate analysis revealed depressive states and age to be independent factors. Therapy for patients with LS should include evaluation and, if necessary, treatment for concomitant depression.


Thermal effects of dorsal head immersion in cold water on nonshivering humans.
Personal floatation devices maintain either a semirecumbent flotation posture with the head and upper chest out of the water or a horizontal flotation posture with the dorsal head and whole body immersed. The contribution of dorsal head and upper chest immersion to core cooling in cold water was isolated when the confounding effect of shivering heat production was inhibited with meperidine (Demerol, 2.5 mg/kg). Six male volunteers were immersed four times for up to 60 min, or until esophageal temperature = 34 degrees C. An insulated hoodless dry suit or two different personal floatation devices were used to create four conditions: 1) body insulated, head out; 2) body insulated, dorsal head immersed; 3) body exposed, head (and upper chest) out; and 4) body exposed, dorsal head (and upper chest) immersed. When the body was insulated, dorsal head immersion did not affect core cooling rate (1.1 degrees C/h) compared with head-out conditions (0.7 degrees C/h). When the body was exposed, however, the rate of core cooling increased by 40% from 3.6 degrees C/h with the head out to 5.0 degrees C/h with the dorsal head and upper chest immersed (P < 0.01). Heat loss from the dorsal head and upper chest was approximately proportional to the extra surface area that was immersed (approximately 10%). The exaggerated core cooling during dorsal head immersion (40% increase) may result from the extra heat loss affecting a smaller thermal core due to intense thermal stimulation of the body and head and resultant peripheral vasoconstriction. Dorsal head and upper chest immersion in cold water increases the rate of core cooling and decreases potential survival time.


Volvulus of the Roux-en-Y hepaticojejunostomy. A rare complication manifested by recurrent ascending cholangitis.
A case of volvulus of a Roux-en-Y hepaticojejunostomy causing recurrent ascending cholangitis is reported. This rare complication of biliary reconstruction was diagnosed preoperatively by percutaneous transhepatic cholangiogram, and successfully treated by resection of the involved segment. The impaired myoelectric activity of the isolated Roux limb may contribute to this pathology.


War injuries of the colon and rectum.
During the war in Croatia, 77 wounded with colon (64) and rectum (13) injuries were treated at Osijek Hospital in the Department of Surgery from June 1991 to September 1992. Shrapnel wounds accounted for 68.8% of the injuries. Forty-seven (61.0%) had unilocular penetrating injury, 15 (19.5%) had multilocular penetrating injuries, 10 (13.0%) had crush injuries, and 5 (6.5%) had contusion of the colon. All who died (14) had associated intra-abdominal and other injuries. Primary repair was possible for 7 (9.1%) injuries, while 4 (5.2%) were repaired and extraperitonealized, 19 (24.6%) exteriorized injuries, 17 (22.1%) were resected followed by oral derivation, 21 (27.2%) sutured followed by oral derivation, and 6 (7.8%) had resection and anastomosis. In 3 (3.9%) patients no colon repair was performed as they died on the table. We had 13 (16.9%) complications and 14 (18.2%) mortalities, 11 (14.3%) postoperatively including 9 within the first 24 h after surgery.


Atorvastatin can ameliorate left atrial stunning induced by radiofrequency ablation for atrial fibrillation.
The objective of this study was to study the functional changes of the left atrium after radiofrequency ablation treatment for atrial fibrillation and the therapeutic effect of atorvastatin. Fifty-eight patients undergoing radiofrequency ablation for atrial fibrillation were randomly divided into non-atorvastatin group and atorvastatin group. Patients in the atorvastatin group were treated with atorvastatin 20 mg p.o. per night in addition to the conventional treatment of atrial fibrillation; patients in the non-atorvastatin group received conventional treatment of atrial fibrillation only. Echocardiography was performed before radiofrequency ablation operation and 1 week, 2 weeks, 3 weeks, and 4 weeks after operation. Two-dimensional ultrasound speckle tracking imaging system was used to measure the structural indexes of the left atrium. Results indicated that there was no significant change for indexes representing the structural status of the left atrium within a month after radiofrequency ablation (P > 0.05); however, there were significant changes for indexes representing the functional status of the left atrium. There were also significant changes in indexes reflecting left atrial strain status: the S and SRs of atorvastatin group were higher than those of non-atorvastatin group (P < 0.05). In summary, atorvastatin could improve left atrial function and shorten the duration of atrial stunning after radiofrequency ablation of atrial fibrillation.


Selective expression of two types of 28S rRNA paralogous genes in the chaetognath Spadella cephaloptera.
Significant intra-individual variation in the sequences of the ribosomal RNA (rRNA) genes is highly unusual in animal genomes; however, two classes of both 18S and 28S rRNA gene sequences have been detected in chaetognaths, a small phylum of marine invertebrates. One species, Spadella cephaloptera Busch, 1851, is well-suited to the methods of in situ analysis of gene expression, since it is totally transparent. To test our hypothesis of a possible functional division of the two classes of genes, we carried out in situ hybridization. Our results indicated that 28S class II genes are expressed intensively in the oocytes of chaetognaths. In contrast, hybridization using an heterologous probe of 28S class I genes revealed only a single and relatively weak signal in a distinct area of intestinal cells. Our results suggest that the S. cephaloptera genome contains at least three different types of rRNA 28S genes; however, those which are expressed during housekeeping conditions could not be detected in our experiments.


The value of modern non-invasive imaging techniques in the elderly.
Computerized tomography, isotope imaging and ultrasonography are available for the investigation of elderly patients at the Middlesex Hospital. Over a six-month period there were 360 acute admissions to the Geriatric Department and 100 specialist imaging techniques were used in their investigation. The pattern of presentation of these patients and results of specialist techniques are presented. Sick elderly patients should have ready access to modern non-invasive imaging techniques.


Copeptin: a neuroendocrine biomarker of COVID-19 severity.
Aim: To investigate the change in a serum level of copeptin, a neuroendocrine biomarker, in differentiating grades of COVID-19 severity on admission time and to find its diagnostic potential. Materials & Methods: 160 COVID-19 patients were classified according to disease severity into 80 mild to moderate and 80 severe patients. Serum copeptin level was assessed by ELISA on their admission time. Besides, serum CRP, ferritin and D-dimer were estimated. Results: Severe COVID-19 patients showed higher serum copeptin level in comparison to mild to moderate cases, with diagnostic potential to distinguish disease severity with 93.33% sensitivity and 100% specificity at cutoff value >18.5 Pmol/l. Conclusion: Serum copeptin was remarkably increased with COVID-19 severity with reasonable differentiation potential for recently admitted patients.


Comparing femtosecond multiphoton dissociative ionization of tetrathiafulvene with imaging photoelectron photoion coincidence spectroscopy.
In this paper we describe femtosecond photoionization and the imaging photoelectron photoion coincidence spectroscopy of tetrathiafulvene, TTF. Femtosecond photoionization of TTF results in the absorption of up to twelve 808 nm photons leading to ion internal energies up to 12.1 eV as deduced from the photoelectron spectrum. Within this internal energy a variety of dissociation channels are accessible. In order to disentangle the complex ionic dissociation, we utilized the imaging photoelectron photoion coincidence (iPEPICO) technique. Above the dissociation threshold, iPEPICO results show that the molecular ion (m/z = 204) dissociates into seven product ions, six of which compete in a 1.0 eV internal energy window and are formed with the same appearance energy. Ab initio calculations are reported on the possible fragment ion structures of five dissociation channels as well as trajectories showing the loss of C2H2 and C2H2S from high internal energy TTF cations. A three-channel dissociation model is used to fit the PEPICO data in which two dissociation channels are treated as simple dissociations (one with a reverse barrier), while the rest involve a shared barrier. The two lower energy dissociation channels, m/z = 146 and the channel leading to m/z = 178, 171, 159, 140, and 127, have E0 values of 2.77 ± 0.10 and 2.38 ± 0.10 eV, respectively, and are characterized by ΔS(‡)(600 K) values of -9 ± 6 and 1 ± 6 J K(-1) mol(-1), respectively. Competing with them at higher internal energy is the cleavage of the central bond to form the m/z = 102 fragment ion, with an E0 value of 3.65 ± 0.10 eV and ΔS(‡)(600 K) = 83 ± 10 J K(-1) mol(-1).


[Lung diseases in the elderly. Pathogenetic significance of pollutants and environmental factors].
In the elderly pneumoconioses due to anorganic or organic dusts are not very common. The incidence of mesothelioma is increasing also in the elderly population. Mesothelioma has become the most frequent occupational malignancy. There is also evidence that mesothelioma can be produced by other fibers than asbestos particles. The paper discusses further the effect of passive smoking, where there is new evidence that passive-smokers are exposed to a higher risk for bronchial cancer than non-smokers. The interactions between smoking and air pollution and morbidity of chronic bronchitis are illustrated. New aspects of pathogenesis and pathophysiology of chronic obstructive lung disease and pulmonary emphysema due to smoking as the most frequent environmental lung disease in the elderly are further discussed. A brief overview of the therapeutical approach to chronic obstructive lung disease including new forms of treatment of cor pulmonale is finally given.


Pilot study of ultrasound parotid imaging reporting and data system (PIRADS): Inter-observer agreement.
To establish proposal ultrasound parotid imaging reporting and data system (PIRADS) for classification and prediction of malignancy of parotid lesions and to assess the inter-observer agreement of this system. Retrospective analysis of ultrasound and power Duplex images of 142 patients with parotid lesions by two reviewers. Parotid focal lesions were classified into nine patterns and then categorized into five groups: PIRADS 1, definitively benign; PIRADS 2, probably benign; PIRADS 3, indeterminate; PIRADS 4, probably malignant; and PIRADS 5, highly suggestive malignant. There was excellent interobserver agreement of both reviewers for patterns and PIRADS (K=0.84, P=0.001) with 92% percent agreement. There was excellent agreement of PIRADS 1 (K=1.00, P=0.001), PIRADS 2 (K=0.97, P=0.001), PIRADS 3 (K=0.86, P=0.001) and PIRADS 5 (K=0.88, P=0.001) and good agreement of PIRADS 4 (K=0.67, P=0.001). The Odds ratio of PIRADS 3, 4 and 5 were 1.36 (95% CI=0.39-4.55), 7.11 (95% CI=3.02-11.15) and 8.27 (95% CI=3.49-10.27) respectively. The accuracy was 92% and 90%, sensitivity was 79% and 65%, specificity was 94% and 96% of PIRADS of both reviewers respectively. The proposed PIRADS is a reliable non-invasive imaging modality that can be used for categorizing parotid lesions and prediction of malignancy.


Meta-analysis and critical review on the efficacy and safety of alpha-glucosidase inhibitors in Asian and non-Asian populations.
To evaluate the efficacy and safety of alpha-glucosidase inhibitors (AGI) in Asian and non-Asian type 2 diabetes patients. Studies were identified through a literature search of MEDLINE, EMBASE and other databases until December 2016. All statistical analyses were carried out in Review Manager statistical software by computing the weighted mean difference or odds ratio and 95% confidence interval. A total of 67 studies were included. AGI vs placebo: compared with the placebo, AGI treatment led to a greater decrease in hemoglobin A1c (HbA1c), fasting plasma glucose and postprandial plasma glucose. No significant difference was observed in HbA1c change, fasting plasma glucose change, postprandial plasma glucose change or incidence of hypoglycemia between Asian and non-Asian patients. AGI vs active controls: in Asian patients, AGI treatment showed a lower reduction in HbA1c compared with dipeptidyl peptidase-4 inhibitors and sulfonylurea. In non-Asian patients, AGI treatment showed a lower reduction in HbA1c compared with thiazolidinedione. No significant difference was observed in HbA1c change and bodyweight change when comparing AGI with other oral hypoglycemic agents between Asian and non-Asian patients. The effects of AGI treatment on glycemic control and bodyweight reduction were superior to the placebo without an increased incidence of hypoglycemia, but with an increased incidence of gastrointestinal discomforts. The hypoglycemic effects of AGI were comparable between Asian and non-Asian patients.


Decision-making in the treatment of elderly people: a cross-cultural comparison between Swedish and German physicians and nurses.
Decision-making in the treatment of elderly people: a cross-cultural comparison between Swedish and German physicians and nurses The aim of the study was to evaluate the comparability of decisions in the treatment of severely ill incompetent elderly patients among physicians and nurses from a cross-cultural perspective. Convenience samples of 192 doctors and 182 nurses from Germany and 104 doctors and 122 nurses from Sweden have been investigated by a questionnaire in a cross-sectional study. Between 39 and 58% of the subjects in the various groups have chosen treatment options, which are not consistent with the patient's will. However, nurses showed a significantly higher compliance than doctors. The probability of choosing cardio-pulmonary resuscitation decreased with increasing information about the patient's wish. Ethical concerns and the patient's wishes appeared as the most important determinants of treatment decisions, whereas the hospital costs as well as the physicians' religion were of minor importance. The inconsistencies concerning decision- making within and between the groups reflect differences in underlying values and lack of societal consensus, which represent a prerequisite for the improvement of patient autonomy. To focus more frequently and to a larger extent onto the problems related to the treatment of severely ill elderly patients as well as onto the training of communication skills with an orientation towards informed consent in the medical training seems to be warranted.


Targeted multidomain intervention for complex mTBI: protocol for a multisite randomized controlled trial in military-age civilians.
Mild traumatic brain injury (mTBI) affects ~18,000 military personnel each year, and although most will recover in 3-4 weeks, many experience persisting symptoms and impairment lasting months or longer. Current standard of care for U.S. military personnel with complex mTBI involves initial (<48 h) prescribed rest, followed by behavioral (e.g., physical activity, sleep regulation, stress reduction, hydration, nutrition), and symptom-guided management. There is growing agreement that mTBI involves different clinical profiles or subtypes that require a comprehensive multidomain evaluation and adjudication process, as well as a targeted approach to treatment. However, there is a lack of research examining the effectiveness of this approach to assessing and treating mTBI. This multisite randomized controlled trial (RCT) will determine the effectiveness of a targeted multidomain (T-MD) intervention (anxiety/mood, cognitive, migraine, ocular, vestibular; and sleep, autonomic) compared to usual care (behavioral management) in military-aged civilians with complex mTBI. This study employs a single-blinded, two-group repeated measures design. The RCT will enroll up to 250 military-aged civilians (18-49 yrs) with a diagnosed complex mTBI within 8 days to 6 months of injury from two concussion specialty clinics. The two study arms are a T-MD intervention and a usual care, behavioral management control group. All participants will complete a comprehensive, multidomain clinical evaluation at their first clinical visit. Information gathered from this evaluation will be used to adjudicate mTBI clinical profiles. Participants will then be randomized to either the 4-week T-MD or control arm. The T-MD group will receive targeted interventions that correspond to the patient's clinical profile (s) and the control group will receive behavioral management strategies. Primary outcomes for this study are changes from enrollment to post-intervention on the Neurobehavioral Symptom Inventory (NSI), Patient Global Impression of Change (PGIC), and functional near-infrared spectroscopy (fNIRS). Time to return to activity (RTA), and healthcare utilization costs will also be assessed. Study findings may inform a more effective approach to treat complex mTBI in military personnel and civilians, reduce morbidity, and accelerate safe return-to-duty/activity. The study is approved by the University of Pittsburgh Institutional Review board and registered at clinicaltrials.gov. Dissemination plans include peer-reviewed publications and presentations at professional meetings. www.clinicaltrials.gov, identifier: NCT04549532.


Preparation of sequence-controlled triblock copolymer-grafted silica microparticles by sequential-ATRP for highly efficient glycopeptides enrichment.
As one of the most important subproteomes in eukaryote cells, N-glycoproteins play crucial roles in various of biological processes and have long been considered closely correlated with the occurrence, progression, and metastasis of cancer. Comprehensive characterization of protein N-glycosylation and association of their aberrant patterns to the corresponding cancer stage may provide a unique way to discover new diagnostic biomarkers and therapeutic drug targets. However, the extremely complex nature of biological samples and relatively low abundance of N-glycosylated proteins makes the enrichment of glycoprotein/glycopeptide a prerequisite for large scale N-glycosylation identification. In this work, we prepared sequence controlled triblock copolymer grafted silica-microparticles (TCP-SMs) by sequential atom transfer radical polymerization (sequential-ATRP) of monosaccharides and zwitterionic-ion monomers for highly efficient and selective glycopeptides enrichment. The triblock copolymer is composed of sequence defined poly zwitterionic-ion, poly-N-acetylglucosamine and poly mannose blocks. The glycopolymer blocks carrying densely packed pendent sugars are excellent mimics of the natural carbohydrate clusters and may induce multivalent carbohydrate-carbohydrate interaction (CCI) with the target glycopeptides. Therefore, increased retention of glycopeptides can be expected by the combination of CCI and zwitterionic-HILIC interaction. As a result, 1244 glycopeptides were identified after TCP-SMs enrichment from mouse liver, which are 65-120% higher than that obtained by homoglycopolymer or random-copolymer grafted silica microparticles prepared using the conventional free radical polymerization. These results demonstrate the critical role of sequence-defined block copolymer of TCP-SMs for obtaining enhanced affinity toward glycopeptides and the potential of this sequential-ATRP strategy to integrate different affinity moieties into one enrichment material to achieve deeper coverage in protein PTM mapping.


Cell-mediated cytotoxicity against HLA-D-region products expressed in monocytes and B lymphocytes. I. Blocking by Unlabelled cells and inhibition by antisera.
Cytotoxic effector cells against HLA-D-region produts were generated in cultures with HLA-A- and B-matched, HLA-D-mismatched stimulating cells. Monocytes from unrelated donors sharing HLA-D/DR antigens with the primary stimulator were used as target cells. Lysis of target cells was inhibited by addition of unlabelled monocytes having the same HLA-D/DR antigens. Inhibition of cytotoxicity was also observed with unlabelled B cells, but T lymphocytes had little effect. The distribution of the target antigens, therefore, fits the known distribution of the products of HLA-D. In other experiments, a human alloantiserum specific for HLA-DRw3 was found to inhibit cellular cytotoxicity specific for HLA-D/DRw3. Lysis by HLA-D/DRw3-specific effector cells was not inhibited by sera against HLA-DRw2 or DRw7 or by antibodies against HLA-B8 using HLA-B8 positive, DRw3 positive targer cells. A xenogeneic serum against human Ia antigens, produced in rabbits, blocked cytotoxicity directed at DRw2, DRw3 and DRw4. These results suggest that cell-mediated cyctotoxicity was directed against HLA-D/DR or very closely associated determinants.


Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis.
Some inherited periodic paralyses are caused by mutations in skeletal muscle Na(V)1.4 sodium channels that alter channel gating and impair action potential generation. In the case of hypokalemic periodic paralysis, mutations of one of the outermost two gating charges in the S4 voltage sensor in domain II of the Na(V)1.4 alpha subunit induce gating pore current, resulting in a leak of sodium or protons through the voltage sensor that causes depolarization, sodium overload, and contractile failure correlated with low serum potassium. Potassium-sensitive normokalemic periodic paralysis (NormoPP) is caused by mutations in the third gating charge in domain II of the Na(V)1.4 channel. Here, we report that these mutations in rat Na(V)1.4 (R669Q/G/W) cause gating pore current that is activated by depolarization and therefore is conducted in the activated state of the voltage sensor. In addition, we find that this gating pore current is retained in the slow-inactivated state and is deactivated only at hyperpolarized membrane potentials. Gating pore current through the mutant voltage sensor of slow-inactivated NormoPP channels would cause increased sodium influx at the resting membrane potential and during trains of action potentials, depolarize muscle fibers, and lead to contractile failure and cellular pathology in NormoPP.


Pulsatile desynchronizing delayed feedback for closed-loop deep brain stimulation.
High-frequency (HF) deep brain stimulation (DBS) is the gold standard for the treatment of medically refractory movement disorders like Parkinson's disease, essential tremor, and dystonia, with a significant potential for application to other neurological diseases. The standard setup of HF DBS utilizes an open-loop stimulation protocol, where a permanent HF electrical pulse train is administered to the brain target areas irrespectively of the ongoing neuronal dynamics. Recent experimental and clinical studies demonstrate that a closed-loop, adaptive DBS might be superior to the open-loop setup. We here combine the notion of the adaptive high-frequency stimulation approach, that aims at delivering stimulation adapted to the extent of appropriately detected biomarkers, with specifically desynchronizing stimulation protocols. To this end, we extend the delayed feedback stimulation methods, which are intrinsically closed-loop techniques and specifically designed to desynchronize abnormal neuronal synchronization, to pulsatile electrical brain stimulation. We show that permanent pulsatile high-frequency stimulation subjected to an amplitude modulation by linear or nonlinear delayed feedback methods can effectively and robustly desynchronize a STN-GPe network of model neurons and suggest this approach for desynchronizing closed-loop DBS.


Influenza A virus uses intercellular connections to spread to neighboring cells.
In the extracellular environment, cell-free virions seek out naive host cells over long distances and between organisms. This is the primary mechanism of spread for most viruses. Here we provide evidence for an alternative pathway previously undescribed for orthomyxoviruses, whereby the spread of influenza A virus (IAV) infectious cores to neighboring cells can occur within intercellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection. Connected cells have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. A live-cell movie of green fluorescent protein (GFP)-tagged NS1 of IAV shows viral protein moving from one cell to another through an intercellular connection. The movement of tagged protein was saltatory but overall traveled only in one direction. Infectious virus cores can move from one cell to another without budding and release of cell-free virions, as evidenced by the finding that whereas a neuraminidase inhibitor alone did not inhibit the development of IAV microplaques, the presence of a neuraminidase inhibitor together with drugs inhibiting actin dynamics or the microtubule stabilizer paclitaxel (originally named taxol) precluded microplaque formation. Similar results were also observed with parainfluenza virus 5 (PIV5), a paramyxovirus, when neutralizing antibody was used to block spread by cell-free virions. Intercellular spread of infectious core particles was unaffected or enhanced in the presence of nocodazole for IAV but inhibited for PIV5. The intercellular connections have a core of filamentous actin, which hints toward transport of virus particles through the use of a myosin motor. Here we describe a new method by which influenza A virus (IAV) spreads from cell to cell: IAV uses intracellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection and the absence of microtubules. Connected cells appeared to have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. Infectious virus cores can move from one cell to another without budding and release of cell-free virions. Similar results were also observed with parainfluenza virus 5 (PIV5).


Specific patterns of immunoreactivity in neuronal elements of the anterior major pelvic ganglion of the male guinea-pig.
The anterior major pelvic ganglion (AMPG) of the male guinea-pig has been found to consist of three principal components. The presence of a cholinergic component was determined by the demonstration of cytoplasmic and nerve fibre acetylcholinesterase activity. A noradrenergic component was demonstrated by immunoreactivity (IR) of the catecholamine-synthesising enzymes tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) in neuronal perikarya. The AMPG also had a peptidergic component which may or may not sub-classify the cholinergic and noradrenergic components. Neuropeptide Y (NPY)-, vasoactive intestinal peptide (VIP)-, and atrial natriuretic factor (ANF)-immunoreactivities were seen in neuronal perikarya, nerve fibres and nerve terminals/varicosities, while somatostatin (SOM)-IR was restricted to neuronal perikarya. Substance P (SP)-IR was present in a dense network of varicose nerve fibres. However, on a rare occasion SP-IR was observed in neuronal perikarya. Enkephalin (ENK)-IR occurred in a sparsely distributed plexus of varicose nerve fibres. The analysis of adjacent serial sections demonstrated distinct patterns of neuropeptide coexistence in AMPG neurons. NPY-IR was colocalised to a subpopulation of TH-IR neuronal perikarya. NPY-IR was also colocalised with VIP-IR in non-TH-IR neuronal perikarya. VIP-IR occurred together with AChE in particular neuronal perikarya. The relationship between immunoreactive neuronal perikarya and immunoreactive nerve terminals was investigated. SP-IR nerve terminals were closely related to neuronal perikarya exhibiting VIP-, NPY-, or TH-IR. TH-IR neuronal perikarya were also abutted by ENK-IR nerve terminals. VIP- and NPY-immunoreactive neuronal perikarya were abutted by two nerve terminal types: one immunoreactive for VIP, the other for NPY. DBH-IR neuronal perikarya received AChE-positive varicosities while AChE-positive neurons were abutted by DBH-IR varicose nerve fibres. AChE-positive varicosities were also closely related to neuronal perikarya possessing VIP-IR and AChE activity.


Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells.
Covalent modifications of histone proteins, in particular deacetylation of lysine residues, are important for the regulation of gene transcription both in normal and malignant cells. These processes are controlled by histone acetyltransferases and histone deacetylases (HDAC) and have up to now not been described in solid mesenchymal tumors. The present study shows differences in the HDAC1 and HDAC2 expression in endometrial stromal sarcomas (ESS) and a cognate cell line (ESS-1) compared with nonneoplastic endometrial stroma. We show for the first time that HDAC2 expression is consistently increased in ESS. In contrast, HDAC1 expression is generally lower than HDAC2 both in nonneoplastic stroma and in ESS, suggesting that these two proteins, although closely related, are regulated in different ways. In vitro experiments with an ESS cell line showed that valproate, an inhibitor of the class I HDACs, led to significant HDAC2 decrease and to cell differentiation. HDAC2 inhibition in ESS-1 cells caused significant changes in the cell cycle by inhibiting G1-S transition and influencing expression of p21WAF1 and cyclin D1. Moreover, in ESS-1 cells, increased expression of the p21WAF1 was associated with reduction of HDAC2 expression after transfection with small interfering RNA directed against HDAC2. Our results suggest that HDAC2 might be considered as potential drug target in the therapy of ESS and that HDAC inhibitors should be further evaluated in clinical trials in ESS.


Nanogel receptors for high isoelectric point protein detection: influence of electrostatic and covalent polymer-protein interactions.
An aldehyde acrylate-based functional monomer was incorporated into poly(N-isopropylacrylamide-co-methacrylic acid) nanogels for use as protein receptors. The aldehyde component forms dynamic imines with surface exposed lysine residues, while carboxylic acid/carboxylate moieties form electrostatic interactions with high isoelectric point proteins. Together, these interactions effect protein adsorption and recognition.


Immunomodulatory Molecule IRAK-M Balances Macrophage Polarization and Determines Macrophage Responses during Renal Fibrosis.
Activation of various innate immune receptors results in IL-1 receptor-associated kinase (IRAK)-1/IRAK-4-mediated signaling and secretion of proinflammatory cytokines such as IL-12, IL-6, or TNF-α, all of which are implicated in tissue injury and elevated during tissue remodeling processes. IRAK-M, also known as IRAK-3, is an inhibitor of proinflammatory cytokine and chemokine expression in intrarenal macrophages. Innate immune activation contributes to both acute kidney injury and tissue remodeling that is associated with chronic kidney disease (CKD). Our study assessed the contribution of macrophages in CKD and the role of IRAK-M in modulating disease progression. To evaluate the effect of IRAK-M in chronic renal injury in vivo, a mouse model of unilateral ureteral obstruction (UUO) was employed. The expression of IRAK-M increased within 2 d after UUO in obstructed compared with unobstructed kidneys. Mice deficient in IRAK-M were protected from fibrosis and displayed a diminished number of alternatively activated macrophages. Compared to wild-type mice, IRAK-M-deficient mice showed reduced tubular injury, leukocyte infiltration, and inflammation following renal injury as determined by light microscopy, immunohistochemistry, and intrarenal mRNA expression of proinflammatory and profibrotic mediators. Taken together, these results strongly support a role for IRAK-M in renal injury and identify IRAK-M as a possible modulator in driving an alternatively activated profibrotic macrophage phenotype in UUO-induced CKD.


Neural stem cell transplantation in ischemic stroke: A role for preconditioning and cellular engineering.
Ischemic stroke continues to be a leading cause of morbidity and mortality throughout the world. To protect and/or repair the ischemic brain, a multitiered approach may be centered on neural stem cell (NSC) transplantation. Transplanted NSCs exert beneficial effects not only via structural replacement, but also via immunomodulatory and/or neurotrophic actions. Unfortunately, the clinical translation of such promising therapies remains elusive, in part due to their limited persistence/survivability within the hostile ischemic microenvironment. Herein, we discuss current approaches for the development of NSCs more amenable to survival within the ischemic brain as a tool for future cellular therapies in stroke.


Loss-of-function of a ubiquitin-related modifier promotes the mobilization of the active MITE mPing.
Miniature inverted-repeat transposable elements (MITEs) are widespread in both prokaryotic and eukaryotic genomes, where their copy numbers can attain several thousands. Little is known, however, about the genetic factor(s) affecting their transpositions. Here, we show that disruption of a gene encoding ubiquitin-like protein markedly enhances the transposition activity of a MITE mPing in intact rice plants without any exogenous stresses. We found that the transposition activity of mPing is far higher in the lines harboring a non-functional allele at the Rurm1 (Rice ubiquitin-related modifier-1) locus than in the wild-type line. Although the alteration of cytosine methylation pattern triggers the activation of transposable elements under exogenous stress conditions, the methylation degrees in the whole genome, the mPing-body region, and the mPing-flanking regions of the non-functional Rurm1 line were unchanged. This study provides experimental evidence for one of the models of genome shock theory that genetic accidents within cells enhance the transposition activities of transposable elements.


[Pancreatic anastomosis -- a video comparison of different techniques].
The pancreatic anastomosis seems to be the most difficult and dangerous anastomosis in general surgery, especially in a soft pancreas. Many techniques have been described. The techniques most often used are: anastomosis of the pancreas to the jejunum as a pancreatico-jejunostomy (duct-to-mucosa anastomosis) or as a pancreato-jejunostomy (invaginating anastomosis). Another widely used anastomosis for reconstruction after pancreatic head resection is from the stomach to the pancreas, i.e., pancreato-gastrostomy. In literature the data concerning postoperative complications (pancreatic fistula, postoperative bleeding and others) are not consistent. Reconstruction after pancreatic head resection. Anastomosis between small intestine or stomach and the pancreas. There is no gold standard for pancreatic anastomosis. Thus, of the different commonly used techniques, in our opinion, the best technique for each surgeon seems to be the one that he/she is most familiar with.


Predator-prey dynamics with disease in the prey.
The Holling-Tanner model for predator-prey systems is adapted to incorporate the spread of disease in the prey. The analysis of the dynamics centers on bifurcation diagrams in which the disease transmission rate is the primary parameter. The ecologically reasonable assumption that the diseased prey are easier to catch enables tractable analytic results to be obtained for the stability of the steady states and the locations of Hopf bifurcation points as a function of the ecological parameters. Two parameters of particular relevance are the ratio of the predator's intrinsic growth rate to the prey's growth rate and the maximum number of infected prey that can be eaten per time. The dynamics are shown to be qualitatively different depending on the comparative size of these parameters. Numerical results obtained with AUTO are used to extend the local analysis and further illustrate the rich dynamics.


Photoinduced tandem reactions of isoquinoline-1,3,4-trione with alkynes to build aza-polycycles.
Photoinduced tandem reactions of isoquinoline-1,3,4-triones (3) with azaaryl substituted acetylenes (4a-4o) are described as an efficient method to build novel aza-polycycles. Most of the reactions proceeded via the tandem reaction sequence of photoinduced [2 + 2] cycloaddition (the Paterno-Büchi reaction)-oxetene electrocyclic ring opening-hexatriene to phenanthrene type electrocyclization-oxidative dehydrogenation. Using these photo tandem reactions of isoquinolinetrione with acetylenes substituted by different azaaryl rings including pyridine, pyrimidine, pyrazine, and quinoline, we were able to obtain diverse aza-polycyclic frameworks with isoquinolinedione fused with naphthalene, quinoline or isoquinoline, quinazoline, quinoxaline, and phenanthridine, respectively, with yields up to 85%. Regioselectivity of the [2 + 2] photocycloadditions and the electrocyclization reactions in the reaction sequence that leads to the formation of different aza-polycyclic ring systems is discussed. Changing the other substitution group on the azaaryl substituted acetylenes from benzene to pyridine or cyclopropane resulted in acetylenes with different photoreactivities with isoquinolinetrione and improved regioselectivity to form single aza-polycyclic products.


Piperine Modulates Protein Mediated Toxicity in Fragile X-Associated Tremor/Ataxia Syndrome through Interacting Expanded CGG Repeat (r(CGG)exp) RNA.
An expansion of CGG tandem repeats in the 5' untranslated region (5'-UTR) of fragile X mental retardation 1 (FMR1) gene causes fragile X-associated tremor/ataxia syndrome (FXTAS). The transcripts of these expanded repeats r(CGG)exp either form RNA foci or undergo the repeat-associated non-ATG (RAN) translation that produces toxic homopolymeric proteins in neuronal cells. The discovery of small molecule modulators that possess a strong binding affinity and high selectivity to these toxic expanded repeats RNA could be a promising therapeutic approach to cure the expanded repeat-associated neurological diseases. Therefore, here we sought to test the therapeutic potential of a natural alkaloid, piperine, by assessing its ability to bind and neutralize the toxicity of r(CGG)exp RNA motif. To accomplish this first, we have determined the affinity of piperine to r(CGG)exp RNA using fluorescence-based binding assay and isothermal titration calorimetry assay. These assays showed that piperine forms a thermodynamically favorable interaction with r(CGG)exp RNA with high selectivity to the G-rich RNA motif. Interaction of piperine with r(CGG)exp motif was further validated using several biophysical techniques such as CD, CD melting, NMR spectroscopy, and gel retardation assay. Moreover, piperine was also found to be effective for improving the r(CGG)exp associated splicing defects and RAN translation in a FXTAS cell model system. Our results effectively provided the evidence that piperine strongly interacts with r(CGG)exp RNA and could be used as a suitable candidate for therapeutic development against FXTAS.


Congenital partial arhinia: a case report.
Congenital arhinia is an extremely rare anomaly consisting of an absence of external nasal structures and nasal passages. Fewer than 30 cases have been reported. Patients with a familial absence of the nose have been reported, but the effects of genetic and maternal factors are unknown. Midface hypoplasia may accompany arhinia. Accompanying malformations are thought to be caused by an absent or rudimentary nose. A patient with partial congenital arhinia is presented and the embryology and literature review are discussed.


Finding subtle motifs by branching from sample strings.
Many motif finding algorithms apply local search techniques to a set of seeds. For example, GibbsDNA (Lawrence et al. 1993, Science, 262, 208-214) applies Gibbs sampling to random seeds, and MEME (Bailey and Elkan, 1994, Proceedings of the Second International Conference on Intelligent Systems for Molecular Biology (ISMB-94), 28-36) applies the EM algorithm to selected sample strings, i.e. substrings of the sample. In the case of subtle motifs, recent benchmarking efforts show that both random seeds and selected sample strings may never get close to the globally optimal motif. We propose a new approach which searches motif space by branching from sample strings, and implement this idea in both pattern-based and profile-based settings. Our PatternBranching and ProfileBranching algorithms achieve favorable results relative to other motif finding algorithms. http://www-cse.ucsd.edu/groups/bioinformatics/software.html


Leveraging ultraviolet photodissociation and spectroscopy to investigate peptide and protein three-dimensional structure with mass spectrometry.
Recent advances in mass spectrometry and lasers have facilitated the development of novel experiments combining the benefits of both technologies. This minireview focuses on the coupling of visible/ultraviolet photons with mass spectrometry for analysis of peptide and protein three-dimensional structure. Practical aspects of instrument design and the relationship between experiment and theory are discussed. Experiments utilizing spectroscopy, action spectroscopy, excitation energy transfer, photodissociation, and photoactivated radical chemistry are described. The strengths and weaknesses of each approach are discussed in relation to the type of information typically obtained. A significant body of data suggests that under appropriate source conditions, kinetically trapped structures are observed in these experiments rather than true gas phase minima, suggesting retention of solution phase structural features is possible. Further refinement and exploration of these methods promises to accelerate protein structure discovery in the near future.


Effects of brain and facial size on basicranial form in human and primate evolution.
Understanding variation in the basicranium is of central importance to paleoanthropology because of its fundamental structural role in skull development and evolution. Among primates, encephalisation is well known to be associated with flexion between midline basicranial elements, although it has been proposed that the size or shape of the face influences basicranial flexion. In particular, brain size and facial size are hypothesized to act as antagonists on basicranial flexion. One important and unresolved problem in hominin skull evolution is that large-brained Neanderthals and some Mid-Pleistocene humans have slightly less flexed basicrania than equally large-brained modern humans. To determine whether or not this is a consequence of differences in facial size, geometric morphometric methods were applied to a large comparative data set of non-human primates, hominin fossils, and humans (N=142; 29 species). Multiple multivariate regression and thin plate spline analyses suggest that basicranial evolution is highly significantly influenced by both brain size and facial size. Increasing facial size rotates the basicranium away from the face and slightly increases the basicranial angle, whereas increasing brain size reduces the angles between the spheno-occipital clivus and the presphenoid plane, as well as between the latter and the cribriform plate. These interactions can explain why Neanderthals and some Mid-Pleistocene humans have less flexed cranial bases than modern humans, despite their relatively similar brain sizes. We highlight that, in addition to brain size (the prime factor implicated in basicranial evolution in Homo), facial size is an important influence on basicranial morphology and orientation. To better address the multifactorial nature of basicranial flexion, future studies should focus on the underlying factors influencing facial size evolution in hominins.


Functions of Polyamines in Mammals.
The content of spermidine and spermine in mammalian cells has important roles in protein and nucleic acid synthesis and structure, protection from oxidative damage, activity of ion channels, cell proliferation, differentiation, and apoptosis. Spermidine is essential for viability and acts as the precursor of hypusine, a post-translational addition to eIF5A allowing the translation of mRNAs encoding proteins containing polyproline tracts. Studies with Gy mice and human patients with the very rare X-linked genetic condition Snyder-Robinson syndrome that both lack spermine synthase show clearly that the correct spermine:spermidine ratio is critical for normal growth and development.


Glucose added to a fat load suppresses the postprandial triglyceridemia response in carriers of the -1131C and 56G variants of the APOA5 gene.
Apolipoprotein A-V plays an important role in the determination of plasma triglyceride (TG) concentration. We aimed to determine whether polymorphisms -1131T>C (rs662799) and 56C>G (rs3135506) of the APOA5 gene have an impact on the course of postprandial lipemia induced by a fat load and a fat load with added glucose. Thirty healthy male volunteers, seven heterozygous for the -1131C variant and three for the 56G variant (HT) carriers, and 20 wild-type (WT) carriers underwent two 8-hour tests of postprandial lipemia - one after an experimental breakfast consisting of 75 g of fat and second after a breakfast consisting of 75 g of fat and 25 g of glucose. HT carriers had a higher postprandial response after fat load than WT carriers (AUC TG: 14.01+/-4.27 vs. 9.84+/-3.32 mmol*h/l, respectively, p=0.016). Glucose added to the test meal suppressed such a difference. Heterozygous carriers of the variants of APOA5 (-1131C and 56G) display more pronounced postprandial lipemia after pure fat load than WT carriers. This statistically significant difference disappears when glucose is added to a fat load, suggesting that meal composition modulates the effect of these polymorphisms on the magnitude of postprandial lipemia.


Improved preparation of ELISA antigen of infectious bursal disease virus.
Serotype 1 of infectious bursal disease virus (IBDV) adapted to chicken embryo fibroblasts (CEF) was used for the preparation of enzyme-linked immunosorbent assay (ELISA) antigen. After several passages of diluted viruses in CEF cultures, the titer of seed virus increased to 1.2 x 10(8) plaque-forming units/ml. Purified virus prepared from this seed virus had high titers of antigen and was less nonspecific than that from low titer of seed virus in an ELISA. The nonspecific reaction of purified virus decreased further after treatment with Triton X-100. When the specificity of this treated antigen was examined with specific-pathogen-free chicken sera before and during lay and with 14 antisera to some major avian viruses, this ELISA antigen had no nonspecific reaction and was specific to antibodies to serotypes 1 and 2 of IBDV.


Characteristic analysis of aspheric quasi-optical lens antenna in millimeter-wave radiometer imaging system.
Quasi-optical imaging systems require low blurring effect and large depth of focus (DOF) to get an acceptable sharpness of the image. To reduce aberration-limited blurring, the aspheric convex plano lenses with an aperture diameter of 350 mm are designed in W-band. We analyzed theoretically and experimentally the millimeter-wave band lens characteristics, such as beam spot size, spatial resolution (SR), and DOF, via f-number. It is first used to verify the DOF through f-number in the system-level test with the developed W-band radiometer imaging system. We have confirmed that the larger f-number of quasi-optical lens leads to a larger DOF but a lower SR.


Successful treatment of acute mania and perineal abscess using dexmedetomidine sedation as adjunctive therapy.
Acute psychiatric illness with agitation presents the clinician with a dangerous, potentially life-threatening situation often requiring complex management. Alteration in patients' insight and judgment may result in medication non-compliance, potentially further complicating therapy directed at the primary psychiatric illness as well as any co-existing conditions. Sedation is often necessary to control dangerous behaviour during the period of antipsychotic and mood-stabilising drug titration. Dexmedetomidine is a centrally acting selective α2-adrenergic agonist with anaesthetic and sedative properties widely used in intensive care units for sedation in critically ill patients. The authors report the case of a patient managed successfully with dexmedetomidine sedation while being treated for acute mania and perineal abscess.


Palmitate enhances protein tyrosine phosphatase 1B (PTP1B) gene expression at transcriptional level in C2C12 skeletal muscle cells.
The factors responsible for regulating PTP1B expression in certain metabolic states have been unclear. We investigated the effects of palmitate on PTP1B gene transcription in C2C12 myotubes and myotubes co-cultured with J774A.1 macrophages. PTP1B mRNA and promoter activity levels were measured in C2C12 myotubes and direct or indirect co-culture of myotubes with macrophages using real time PCR and luciferase activity, respectively. Palmitate significantly induced PTP1B mRNA and promoter activity levels 1.36- and 1.32-fold, respectively, in C2C12 cells compared with the untreated myotubes. Palmitate showed a 2.3-fold increase in PTP1B mRNA level in myotubes co-cultured indirectly with macrophages. PTP1B promoter activity was also significantly induced by palmitate in direct (1.8-fold) and indirect (1.48-fold) co-culture of myotubes with macrophages. These data suggest that while palmitate treatment significantly induced PTP1B expression at the transcriptional level, the presence of an inflammatory process exerted by macrophages can augment this effect in the muscle cells.


Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer.
The balance of proinflammatory cytokines interleukin (IL)-12 and IL-23 plays a key role in shaping the development of antitumor or protumor immunity. In this review, we discuss the role IL-12 and IL-23 plays in tumor biology from preclinical and clinical data. In particular, we discuss the mechanism by which IL-23 promotes tumor growth and metastases and how the IL-12/IL-23 axis of inflammation can be targeted for cancer therapy.


Paraproteinaemia: use of idiotypic determinants as specific markers for tumour activity.
Five patients with paraproteinaemia were investigated using anti-idiotype antibodies specific for their paraproteins. Sensitive assays were used to detect soluble paraprotein either in serum or in supernatants from cultures of peripheral blood mononuclear cells (PBMC) and bone marrow cells. It was found that (i) measurement of serum paraprotein by specific radioimmunoassay is a sensitive method of monitoring the course of multiple and solitary myeloma, (ii) morphologically normal bone marrow from a multiple myeloma patient contained paraprotein-secreting plasma cells, (iii) a patient with benign monoclonal gammopathy had at least one stage in her disease where pre-plasmacytic tumour cells were present in the peripheral blood, (iv) the PBMC of the patients with active myeloma contained suppressor monocytes, and (v) PBMC from treated myeloma patients (both those with still active disease and those in apparently complete remission) would not secrete paraprotein in culture under a variety of different culture conditions including partial monocyte depletion.


Assessing connectivity related injury burden in diffuse traumatic brain injury.
Many of the clinical and behavioral manifestations of traumatic brain injury (TBI) are thought to arise from disruption to the structural network of the brain due to diffuse axonal injury (DAI). However, a principled way of summarizing diffuse connectivity alterations to quantify injury burden is lacking. In this study, we developed a connectome injury score, Disruption Index of the Structural Connectome (DISC), which summarizes the cumulative effects of TBI-induced connectivity abnormalities across the entire brain. Forty patients with moderate-to-severe TBI examined at 3 months postinjury and 35 uninjured healthy controls underwent magnetic resonance imaging with diffusion tensor imaging, and completed behavioral assessment including global clinical outcome measures and neuropsychological tests. TBI patients were selected to maximize the likelihood of DAI in the absence of large focal brain lesions. We found that hub-like regions, with high betweenness centrality, were most likely to be impaired as a result of diffuse TBI. Clustering of participants revealed a subgroup of TBI patients with similar connectivity abnormality profiles who exhibited relatively poor cognitive performance. Among TBI patients, DISC was significantly correlated with post-traumatic amnesia, verbal learning, executive function, and processing speed. Our experiments jointly demonstrated that assessing structural connectivity alterations may be useful in development of patient-oriented diagnostic and prognostic tools. Hum Brain Mapp 38:2913-2922, 2017. © 2017 Wiley Periodicals, Inc.


[Sonographic imaging and assessment of stomach wall changes].
By the use of a special method of investigation, the true value of percutaneous echography was investigated using 28 patients with primary gastric neoplasms and 3 patients with secondary infiltration of the gastric wall, for the proof and the judgement of the tumors, their extension and their metastases. Tumorous gastric wall thickening could be demonstrated in 87% (27/31), tumor invasion in neighbouring structures in 85% (12/14) and lymph nodes metastases in 66% (10/15). In all patients, who had liver metastases (4) or ascites (5) they were demonstrable. The sonographic appearance of the different gastric wall changes are described and discussed.


Unintended effects in settings-based health promotion.
The settings-based approach to health promotion (HP) employs a social ecological (SE) framework to integrate HP into the usual activities of the setting and to increase the setting's support for healthy choices. The SE approach calls for systems thinking to account for the inextricable relationship between people, their behaviour and their environment. Knowledge about a setting can be used to mobilise people to participate in HP, to optimise success by taking into account the local context, and to anticipate and avoid barriers to success. In other words, the SE approach aims to help HP reach its goals for better health, established in concert with community needs and wishes. Yet, the focus on HP goals may detract attention from how intervention may have unanticipated, and even untoward effects on the setting. There is much evidence from classical ecological research that well-meaning interventions have unintended effects. Biology is so tuned to the possibility that the study of unintended effects is integral to the field. There is some evidence--but much less--that HP also has unexpected, deleterious effects. The evidence is limited because of neglect; the subject of unintended effects is only of peripheral interest in HP. This is a call for a more robust SE approach, in which frameworks used to guide settings-based HP are augmented so as to be concerned with planned effects, and also unplanned effects. What can be done to more responsibly monitor, document and report the full panoply of our effects, including detecting and preventing untoward effects?


Fine-needle aspiration cytology of tumors: diagnostic accuracy and potential pitfalls.
FNA biopsy is a quick, safe, and inexpensive method for obtaining material for pathological diagnosis. It is most useful in the diagnosis of a malignant tumor. In experienced hands it is highly accurate, and many of the pitfalls in cytological interpretation can be avoided with increased practice. Special training is required to become proficient in both obtaining and interpreting aspirated material. It is not sufficient for pathologists to apply personal experience from tissue pathology to the diagnosis of cytological specimens. Current indications are the FNA biopsy will be used with increasing frequency for reasons involving both clinical practice and cost containment.


Successfully treated case of severe hypothermia secondary to myxedema coma.
Myxedema coma is an extremely rare but fatal endocrine emergency that requires urgent recognition and treatment. We describe a case of severe hypothermia that rapidly deteriorated to cardiac arrest that was attributed to myxedema coma. A 52-year-old man without a history of hypothyroidism was transferred to our emergency department due to coma and profound hypothermia. The patient developed cardiac arrest immediately after hospital arrival but return of spontaneous circulation was achieved shortly after resuscitation. The patient was noted to have generalized, nonpitting edema, dry skin, severe respiratory acidosis, hyponatremia, and elevated creatinine kinase, which was indicative of hypothyroidism. Myxedema coma was confirmed by a thyroid profile. The patient was successfully treated with intravenous levothyroxine and glucocorticoid. Although myxedema coma is a rare cause of severe hypothermia, emergency physicians should be familiar with its clinical features and management.


Acute Thrombosis of an Aortic Prosthetic Graft in a Patient with Severe COVID-19-Related Pneumonia.
COVID-19 infection has been reported to be related with an increased risk of thrombotic complications because of the hypercoagulability state and inflammation. At the moment, no reports are available regarding thrombosis of prosthetic vascular grafts. We present the case of a patient with COVID-19-related pneumonia, who suffered from the acute thrombosis of a previously implanted aortic graft. A 67-year-old male patient, who had undergone open repair of an abdominal aortic aneurysm with a bifurcated graft 6 years before, was admitted to the emergency department with high fever for a week without cough or dyspnea. Thoracic ultrasound showed signs of bilateral interstitial pneumonia, and the Sars-Cov-2 swab was positive. Antiretroviral therapy and prophylactic low molecular weight heparin treatment were initiated. Owing to the progressive impairment of the respiratory function, the patient was intubated after eight days from the admission, the day after he showed signs of bilateral acute limb ischemia. A duplex ultrasound demonstrated the complete thrombosis of the aortic graft without flow at the femoral level. An urgent angio-computed tomography scan for revascularization purpose was requested, but the patient died on the arrival in the radiological suite. Acute thrombosis of vascular prosthetic grafts is a possible, catastrophic complication of COVID-19 infection. In COVID-19 patients with prosthetic graft, an aggressive antithrombotic treatment could be considered to prevent such an event.


Coronary artery revascularization after myocardial infarction.
Authors report on the revascularization resulted by noninvasive and invasive interferences carried out 6-9 months after surgery and on the improvement of functional status of 56 postinfarction patients with recurrent angina pectoris. They conclude that recoronarography performed in 12 patients revealed diminished patency rate as compared to the estimated rate, especially in those cases, where complete revascularization was considered to have been carried out. Ejection fraction, wall motion score by ventriculography and echocardiography did not seem to improve significantly. However Dipyridamole Thallium scintigraphy showed marked improvement in perfusion in all cases. NYHA functional status noticeably improved in the re-examined patients.


Sexual differentiation of the brain and behavior.
During the intrauterine period the human brain develops in the male direction via direct action of a boy's testosterone, and in the female direction through the absence of this hormone in a girl. During this time, gender identity (the feeling of being a man or a woman), sexual orientation, and other behaviors are programmed. As sexual differentiation of the genitals takes places in the first 2 months of pregnancy, and sexual differentiation of the brain starts during the second half of pregnancy, these two processes may be influenced independently of each other, resulting in transsexuality. This also means that in the case of an ambiguous gender at birth, the degree of masculinization of the genitals may not reflect the same degree of masculinization of the brain. Differences in brain structures and brain functions have been found that are related to sexual orientation and gender.